title: Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing.
abstract: Hereditary hearing loss is genetically heterogeneous, with a large number of genes and mutations contributing to this sensory, often monogenic, disease. This number, as well as large size, precludes comprehensive genetic diagnosis of all known deafness genes. A combination of targeted genomic capture and massively parallel sequencing (MPS), also referred to as next-generation sequencing, was applied to determine the deafness-causing genes in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. Among the mutations detected, we identified nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA, doubling the number of myosin mutations in the Middle East. Myosin VI mutations were identified in this population for the first time. Modeling of the mutations provided predicted mechanisms for the damage they inflict in the molecular motors, leading to impaired function and thus deafness. The myosin mutations span all regions of these molecular motors, leading to a wide range of hearing phenotypes, reinforcing the key role of this family of proteins in auditory function. This study demonstrates that multiple mutations responsible for hearing loss can be identified in a relatively straightforward manner by targeted-gene MPS technology and concludes that this is the optimal genetic diagnostic approach for identification of mutations responsible for hearing loss.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Zippora
authors.initials: Z
authors.lastname: Brownstein
authors.affiliation: Department of Biological Sciences, Bethlehem University, Bethlehem, Palestine.
authors.forename: Amal
authors.initials: A
authors.lastname: Abu-Rayyan
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Daphne
authors.initials: D
authors.lastname: Karfunkel-Doron
authors.affiliation: Structural Motility, Institut Curie, UMR 144, CNRS, Paris, France.
authors.forename: Serena
authors.initials: S
authors.lastname: Sirigu
authors.affiliation: Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
authors.forename: Bella
authors.initials: B
authors.lastname: Davidov
authors.affiliation: 1] Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel [2] Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel.
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.affiliation: 1] Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel [2] Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.affiliation: Structural Motility, Institut Curie, UMR 144, CNRS, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Houdusse
authors.affiliation: Department of Biological Sciences, Bethlehem University, Bethlehem, Palestine.
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D018912:Arabs / Q000235:genetics; D001483:Base Sequence; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D023281:Genomics / Q000379:methods; D034381:Hearing Loss / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007557:Israel; D007585:Jews / Q000235:genetics; D008297:Male; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: C485245:MYO15A protein, human; C000631455:MYO7A protein, human; D000081412:Myosin VIIa; C089785:myosin VI; D018995:Myosin Heavy Chains; D009218:Myosins